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MODA > Dr van Veen - Chemotherapy > Flashcards

Dr van Veen - Chemotherapy Flashcards

0
Q

What are narrow spectrum antibiotics?

A

Those which are mainly effective against either Gram-negative or Gram-positive bacteria

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1
Q

What are broad spectrum antibiotics?

A

Those which target a wide range of Gram-positive and Gram-negative bacteria

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2
Q

What are limited spectrum antibiotics?

A

Those which are effective against a single organism or disease

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3
Q

What are the features of later generations of semisynthetic variants of antibiotics

A

Increased oral bioavailabililty
Increased stability
broader spectrum (extended spectrum)
Efficacy against resistant microorganisms

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4
Q

What are the five main classes of antibiotics?

A 
Cephalosporins
Macrolides
β-lactamase inhibitors
Penicillins
Quinolones
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5
Q

What are the two general categories of antibiotic action?

A

Bacteriostatic vs bactericidal

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6
Q

Give an example of a bacteriostatic and a bactericidal antibiotic

A
  • cidal = penicillin

- static = chloramphenicol

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7
Q

What are two measures of effectiveness of a chemotherapeutic drug?

A

Minimal inhibitory concentration

Minimal bactericidal concentration

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8
Q

What are the major targets of anitbiotic action?

A 
Cell wall biosynthesis
Protein biosynthesis
DNA replication, repair and expression
Folate coenzyme biosynthesis
(Also in some cases membranes can be the target)
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9
Q

Explain the biosynthesis of peptidoglycans

A
  1. UTP and three amino acids joined to N-acetylglucosamine => UDP N-acetyl muramyl-tripeptide
  2. D-Ala-D-Ala is joined to produce UDP N-acetyl muramyl pentapeptide
  3. UDP N-a m pp is then joined to UDP N-acetylglucosamine (also linked to bactoprenol phosphate via a phosphate bridge = association with the inner leaflet of the phospholipid bilayer and transports it to the outer leaflet)
  4. PG repeat units are joined to make a polymer and bactoprenol carrier is detached
  5. PG polymers cross linked by peptidoglycan transpeptidase
  6. Reorientation of bactoprenol pyrophosphate to the inner membrane surface and its dephosphorylation to bactoprenol phosphate
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10
Q

D-cycloserin

A

Antibiotic that is a structural analogue of D-alanine

Prevents formation of the pentapeptide through inhibition of

  • L-alanine racemase
  • D-alanyl-D-alanine synthetase
  • Ligase that connects the D-alanyl-D-alanine unit to the muramyl-tripeptide (possibly)
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11
Q

Fosfomycin

A

Antibiotic that inhibits cell wall biosynthesis through inhibition of pyruvyl transferase

(transfers the phosphoenolpyruvate group to UDP N-acetylglucosamine in the production of UDP N-acetyl muramyl-tripeptide)

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12
Q

Penicillin

A

β-lactam antibiotic

Inhibits the PG-cross-linking transpeptidases

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13
Q

Ampicillin

A

β-lactam antibiotic

Inhibits the PG-cross-linking transpeptidase

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14
Q

What kind of enzyme are transpeptidases? How do they work in cell wall biosynthesis?

A

All variants of ‘serine’ hydrolases

  • Attack of the active site serine on the amide bond between the two D-Alas
  • Acyl transfer to amino moiety of diaminopimelic acid of L-lysine-(glycine) in a neighbouring pentapeptide = cross-linking

-The adduct then collapse to an acyl-O-ser enzyme with release of D-Ala

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15
Q

How do β-lactam function?

A

They inhibt transpeptidase enzymes causing them to commit suicide when they start the catalytic cycle with β-lactam antibiotics

Binds to the active site serine - cannot be hydrolysed as water is excluded from the active site

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16
Q

Vancomycin

A

Binds to pentapeptide tails in the PG repeating unit terminating in D-Ala-D-Ala = transpeptidase enzyme cannot access it

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17
Q

What is the structure of the bacterial ribosome?

A

Two-subunit nucleoprotein (30S and 50S)

2/3 RNA and 1/3 protein

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18
Q

Explain initiation of bacterial protein synthesis

A

Formation of the initiation complex - mRNA becomes attached to the 30S subunit (requires intiation factor 3)

formylmethione-charged tRNA then combines with the mRNA-30S ribosomal complex (require initiation factors 1 and 2, and GTP)

50S binds bound GTP is hydrolysed and initiation factors are released

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19
Q

Explain the continuation of bacterial protein synthesis

A

Accomplished by repetition of three reactions
50S joins aminoacids on the tRNA through its peptidyltransferase activity and the peptide is attached to the second tRNA
First tRNA moves to exit site (from P site) and is released
tRNA with dipeptide moves from A to P site

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20
Q

Tetracycline

A

Broad spectrum antibiotic - used as first line treatment against Mycoplasma sp. and Vibrio cholera

Reversibly binds to the 30S ribosome and inhibits the entry of aminoacyl-tRNA into the acceptor site with the help of bound Mg2+

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21
Q

Where is the binding site of tetracycline? How does this binding occur?

A

30S subunit in a 20A wide and 7A deep groove containing rRNA

The oxygens of the internucleotide phosphodiester links in 16S rRNA form electrostatic interactions, directed through Mg2+

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22
Q

What is the structure of aminoglycosides? Upon which bacteria are they effective?

A

Consist of 2 or more sugars linked to an aminocyclitol ring by glycosidic bonds

Narrow spectrum; active uptake in aerobic Gram-negative rods (also act upon some G+ bacteria)

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23
Q

What is special about the aminoglycoside antibiotics? Which antibioitics does this inclue

A

They are bactericidal (most protein synthesis inhibitors are purely static) because they insert the ‘wrong’ amino acid in proteins

Streptomycin and gentamycin

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24
Q

Streptomycin

A

Aminoglycoside bactericidal antibiotic (narrow spectrum)

Binds to the 30S ribosomal subunit and freezes the pre-initiation complex Also slows down protein synthesis and can induce misreading

Effective against G- rods (actively taken up)

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25
Q

Upon what do macrolides act?

A

The 50S subunit of the bacterial ribosome

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26
Q

Erythromycin

A

Antibiotic

Inhibits the 50S subunit of the bacterial ribosome by binding to the entrance of the polypeptide exit tunnel

Allows 6-8 oligopeptidyl-tRNA build up before elongation is blocked

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27
Q

Chloramphenicol

A

Broad spectrum antibiotic

Binds to the 50S subunit and inhibits aminoacyl-tRNA binding at the P site

Emergency drug - Sever toxicity

Used in the treatment of bacterial meningitis (haemophilus influenza or Neisseria meningitidis)

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28
Q

Fusidic acid

A

Narrow spectrum antibiotic

Inhibits elongation factor G

Fewer toxic effects than other protein synthesis inhibitors

Narrow spectrum skin and eye infections by G+ bacteria

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29
Q

Puromycin

A

Antibiotic that resembles the 3’ end of tyrosyl-tRNA

Enters the A site no the ribosome and transfers to the growing polypeptide chain at the P site causing premature chain termination

Used experimentally

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30
Q

What are the three ways in which antibiotics can act on DNA replication and gene expression?

A

Inhibitors of type II topoisomerases

Inhibitors of RNA synthesis

Compounds that interact with dsDNA

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31
Q

What are the inhibitors of type II DNA topoisomerases?

A

Aminococumarins

Quinoiones

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32
Q

Fluoroqiunolones

A

Synthetic broad spectrum bactericidal antibiotics

Topoisomerase inhibitors

Used in the treatment of Pseudomonas infections (eg cystic fibrosis patients)

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33
Q

Ciprofloxacin

A

Synthetic broad spectrum bactericidal antibiotics

Topoisomerase inhibitors

Used against Bacillus anthrax infections

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34
Q

Levofloxacin

A

3rd gen Fluoroquinolone antibiotic

Broad spectrum and bactericidal

Improved activity against Strep pn.

Really expensive

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35
Q

Rifampin

A

Antibiotic

Binds to β subunit of DNA dep RNA pol of bacteria

Blocks elongation of RNA chain at the stage of initiation by binding to RNA transport tunnel

Used in Myco tuberculosis infections

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36
Q

Bleomycin

A

Antibiotic

Metal-chelating glycopeptide (produces oxygen radicals)

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37
Q

Daunomycin

A

Planar antibiotic molecule that intercalates between nucleobases of duplex DNA

Prevents normal transcription of DNA

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38
Q

Mitomycin C

A

Aziridine antibiotic that acts upon dsDNA

Alkylating agent induces cross-linking between Gs at trans positions in dsDNA

Also shown to act as an anticancer drug (activated through reduction quinone group)
- Alkylation and crosslinking of DNA

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39
Q

Streptomycin

A

Antibiotic

Binds to the 30S subunit

Causes insertion of the wrong amino acid into synthesised proteins

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40
Q

Where does tetracycline bind?

A

30S subunit in rRNA in a groove of 20A wide and 7A deep

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41
Q

Lincomycin

A

Antibiotic

Direct peptidyltransferase inhibitor of bacterial ribosomes

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42
Q

What is the target of quinolones?

A

DNA gyrase (type II topoisomerase)

Also DNA topoisomerase IV

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43
Q

Gentamicin

A

Antibiotic

Binds to the 30S subunit

Causes insertion of the wrong amino acid into synthesised proteins

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44
Q

Sulfamethoxazole

A

Antibiotic

Inhibits dihydropteroate synthase (folic acid synthesis)

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45
Q

Valinomycin

A

Antibiotic

Contains three repeating units of (L-lactate)-(L-valine)-(D-hydroxyisovalerate)-(D-valine) which forms a circle

Carries K+ across the membrane

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46
Q

Trimethoprim

A

Antibiotic

Inhibits dihydrofolate reductase (folic acid synthesis)

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47
Q

Gramicidin A

A

Antibiotic

Hydrophobic linear polypeptide antibiotic with 15 aa and a carboyterminal ethanolamine

Dimerises in the membrane to form an ion channel

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48
Q

What is the target of polyenes?

A

Cell membranes - binding to ergosterol and allowing pore formation

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49
Q

Polymixin

A

Antibiotic - cyclic amphipatic protein with a net charge of 5+

Associates with negatively charged phosphate head groups on the outer surface of the membrane, and then, to aggregate into micelle-like complexes which bind lipids and affect permeability

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50
Q

Amphotericin B

A

Antibiotic

Binds to ergosterol and facilitates formation of pores for ions and macromolecules

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51
Q

What is the most important distinction of pharmacological significance to the treatment of parasitic infections? Why is this important?

A

Whether the infecting organism is unicellular protozoan or multicellular helminth

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52
Q

Melarsen

A

Organic arsenical used against trypanosomes (actively accumulated)

Inhibits lipoic acid-dependent enzymes
Inhibits dithiol containing metallo-enzymes

Affects ATP synthesis

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53
Q

Suramin

A

Development of Ehrlich’s Trypan Red

First useful anti-trypanosomal drug without a toxic metal atom

Only effective in early stages as drug does not cross BBB

Mechanism unknown (may be based on inhibition of glycolytic enzymes)

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54
Q

What are the drugs used against Leishmaniasis?

A

Amphotericin B affects membrane permeability

Miconazole inhibits ergosterol biosynthesis

(Leishmania sp’s membranes contain ergosterol

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55
Q

What do Plasmodium use as a nitrogen source? Why is this important?

A

Haemoglobin

Would accumulate to toxic levels if it wasn’t polymerised into non-toxic hemozoin
target of chloroquine

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56
Q

Chloroqiune

A

Antimalarial drug

Inhibits the formation of haemozoin (product of their digestion of haemoglobin) resulting in toxic levels of haem (produces ROS)

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57
Q

Mefloquine

A

Antimalarial drug

Inhibits the formation of haemozoin (product of their digestion of haemoglobin) resulting in toxic levels of haem (produces ROS)

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58
Q

Artemisinin

A

Antimalarial agent

Inhibits development of oocysts in mosquitos

Generates highly reactive organic free radicals using peroxide bridge (might inhibit parasite ETC (Cyt b) or SERCA pump)

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59
Q

What is a potential target for the treatment of malaria?

A

Drugs could be used to block the link between the exo-erythrocytic stage thus preventing infection

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60
Q

Draw the malarial life cycle and label the potential sites of drug action

A

Sporogenic cycle
Exo-erythrocytic cycle
Erythrocytic cycle

Act on liver schizont (tafenoquine and primaquine)
Act on oocyst
Act on growth in erythrocytes
Chemoprophylaxis

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61
Q

Sulfadoxine

A

Antimalarial agent

p-aminobenzoate analogue used to inhibit the action of dihydropteroate synthase

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62
Q

Pyrimethamine

A

Antimalarial agent

Trimethoprim analogue that inhibits dihyrofolate reductase

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63
Q

Fansidar

A

Antimalarial agent containing sulfadoxin and pyrimethamine used against P. falciparum

Inhibits both DHFR and DHPS

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64
Q

Proguanil

A

Prophylactic antimalarial prodrug

Converted to cycloguanil which inhibits plasmodial dihydrofolate reductase

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65
Q

What two classes of antibiotic have shown activity against certain protozoa?

A

Tetracylcines and lincomycins

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66
Q

What are the targets of antiviral chemotherapies?

A

Agents that inactivate intact viruses (virucidal)

Agents that modify the host’s response to infection (immunomodulating)

Agents that inhibit viral replication at the cellular level (antiviral)

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67
Q

Amantadine

A

Antiviral drug used in the treatment of influenza

Early stages - Blocks the function of the M2 channel protein

Later stages - Interferes with haemagglutinin processing (prevents conformational change)

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68
Q

Oseltamivir

A

Ethyl ester pro-drug used in the treatment of influenza (activated by esterases in the plasma)

Inhibits the neuraminidase of Influenza A and B

Enhances viral aggregation and inhibits release from host cells

Also reduces movement of virus particles through the upper respiratory tract

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69
Q

Zanamivir

A

Drug used in the treatment of influenza

Inhibits the neuraminidase of Influenza A and B

Enhances viral aggregation and inhibits release from host cells

Also reduces movement of virus particles through the upper respiratory tract

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70
Q

Draw a cycle of influenza infection and the site at which drugs can inhibits this

A

Well done

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71
Q

Upon what do all available antiherpesvirus agents work

A

The virally encoded DNA polymerases that replicate the dsDNA genome of the virus

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72
Q

Aciclovir

A

Antiherpes drug that inhibits its DNA polymerase

Monophosphorylated by thymidine kinase and then acts as a chain terminator = permanent inactivation of enzyme

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73
Q

How is aciclovir selective for virally infected cells?

A

Only virally infected cells have the thymidine kinase needed to monophosphorylate the drug

The drug preferentially binds to the virally encoded DNA pol (30x higher affinity)

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74
Q

Ganiciclovir

A

Drug used in the treatment of CMV (phosphorylated by phosphotransferase encoded by CMV)

Competitive inhibitor of DNA polymerase (but has 3’ OH moieties)

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75
Q

Cidofovir

A

Nucleoside phosphate analogue of cytosine

Converted to a diphosphoryl derivative that selectively inhibits the DNA polymerase of CMV

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76
Q

What are the pyrimidine analogues used in the treatment of herpes virus? How do they function

A

Trifluridine and idoxuridine

Both inhibit DNA polymerase (but greater toxicity so applied topically)

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77
Q

Foscarnet

A

Organic analogue of pyrophosphate

Selectively binds to viral DNA polymerase of CMV and HSV and prevents the cleavage of PPi from nucleoside triphosphate during DNA pol

78
Q

What are the three kinds of anti HIV agents?

A

Inhibitors of viral fusion
Reverse transcriptase inhibitors
Protease inhibitors

79
Q

Nevirapine

A

Anti HIV agent

Binds to reverse transcriptase near catalytic site and denatures it

80
Q

Zidovudine

A

Anti HIV agent

Binds to reverse transcriptase and acts as a chain terminator (lack of a 3’OH)

Phosphorylated to active form

81
Q

Azidothymidine (AZT)

A

Anti HIV agent

Binds to reverse transcriptase and acts as a chain terminator (lack of a 3’OH)

Phosphorylated before becoming active
Valyl ester increases bioavailability

82
Q

Why is hydroxyurea often co-administered with pyrimidine analogues?

A

Inhibits ribonucleotide reductase thereby decreasing the intracellular pool of pyrimidine nucleotides and potentiating the effects of pyrimidine analogues

83
Q

How do HIV protease inhibitors function?

A

Aspartyl protease converts polypeptides into functioning proteins by cleavage at appropriate positions

Inhibition means that newly produced viruses are not infectious as protease is required during virus budding

84
Q

Saquinavir

A

HIV protease inhibitor

Binds to the two Asp residues of the protease

Prevents the formation of infectious virus particles

85
Q

Interferon-α-2a

A

Used in the treatment of hep B and AIDS related Kaposi sarcomas

Low bioavailability so administered intralesionally, SC and IV

Acute flu-like symptoms

86
Q

What are the ways in which anticancer drugs can act?

A

By preventing effective DNA replication through direct binding to nucleobases or impairing the DNA synthesis machinery

By damaging the mechanisms of cell division such as formation of the mitotic spindles

By blocking the pathways involved in cell growth that are activated by signals such as growth factors of hormones

87
Q

What are the side effects of targeting rapidly proliferating cells?

A 
Hair loss
Depression of gametogenesis
Bone marrow suppression
Nausea and vomiting
GI disturbance
88
Q

How do nitrogen mustards act as anticancer agents?

A

Crosslinks are formed between or within DNA strands

Second reaction can occur with water resulting in GC to AT transition

Can also occur with other nucleophilic groups (RNA and protein) = general toxicity

89
Q

Cyclophosphamide

A

Nitrogen mustard anti cancer drug

Causes cross linking of DNA strands through the generation of a carbonium ion

Taken orally

Metabolised by the liver by P450 to become activated to a phosphoramide mustard

90
Q

Melphalan

A

Anti cancer drug used against melanomas

Nitrogen mustard attached to phenylalanine = taken up by melanomas (phenylalanine is precursor to melanin

Taken orally

91
Q

Lomustine

A

Nitrosourea compound used as an anticancer drug

Proposed to act through alkylation of proteins and DNA following generation of an isocyanate molecule and a 2-Chloroethyl diazene hydroxide

92
Q

How do aziridines act as anticancer drugs?

A

DNA alkylation and cross linking

Activated by chemical or enzymatic reduction of the quinone group

93
Q

Cis-diamine dichloroplatinum (cisplatin)

A

Anti cancer drugs

Cross linking agent in DNA (site of action are N7 atoms of guanine and adenine)

Small size therefore can only cross link within strands (2Gs)

Only given IV

Has renal toxicity

94
Q

How do anticancer drugs that damage DNA cause cell death?

A

Through the activation of p53

95
Q

Doxorubicin

A

Antracyclin anticancer drug

Intercalates with DNA

Also induces oxidative damage to DNA which results in DNA fragmentation

Severe side effects in cardiac tissue due to lipid peroxidation

96
Q

Daunomycin

A

Antracyclin anticancer drug

Intercalates with DNA

Also induces oxidative damage to DNA which results in DNA fragmentation

Severe side effects in cardiac tissue due to lipid peroxidation

97
Q

Mitoxantrone

A

Antracyclin anticancer drug

Intercalates with DNA and inhibits topoisomerase type II

Does not result in free radical generation

Used in breast cancer, acute myeloid leukemia and certain lymphomas

98
Q

Methotrexate

A

Antimetabolite used as an anticancer drug

Inhibits the enzyme dihydrofolate reductase = prevents folate synthesis

Also competes with folic acid for active transport into mammalian cells

Given with leuvocovorin in order to salvage normal tissue from folate depletion (= reduced toxicity

99
Q

5-fluorouracil

A

Converted in cells into 5-flurouracil-2’-deoxyuridine

Then can inhibit thymidine synthetase

Often given with leucovorin (potentiates action)

100
Q

Leuvocovorin

A

Given with methotrexate in order to salvage normal tissue from folate depletion

Also given with 5-flurouracil to potentiate its action

101
Q

What are the inhibitors of topoisomerases?

A

Type I - Camptothecin and topotecan

Type II - etoposides, antracyclines, mitoxantrone and epipodophyllotoxins

102
Q

How does the herpes virus DNA polymerase function?

A

DNA chain is lengthened as the phosphate group at the 5’ carbon of the sugar of one nucleotide subunit is linked to the OH group of the 3’ carbon of the sugar of the next nucleotide
(releases PPi)

103
Q

Camptothecins?

A

Anticancer drug

Topoisomerase type I inhibitor

104
Q

Topotecins?

A

Anticancer drug

Topoisomerase type I inhibitor

105
Q

Etoposides

A

Anticancer drug

Topoisomerase type II inhibitor

106
Q

Epipodophyllotoxins

A

Anticancer drug

Topoisomerase type II inhibitor

107
Q

Microtubules?

A

Protein polymer that is responsible for various aspects of cellular morphology and movement. Also involved in mitosis (pull the chromosomes by attaching to the spindles

Oscillate between polymerisation and depolymerisation (=equilibrium)

Target for anticancer drugs

108
Q

Vinblastine

A

Vinca alkaloid

Anti cancer drug that binds to tubulin dimer, leading to disassembly of microtubules

This disrupts cell division

109
Q

Taxol (paclitaxel)

A

Anticancer drug that bind microtubule, and thereby stabilise these structure

This disrupts cell division

110
Q

How can steroid hormones be used against certain cancers? What kinds of cancer can this be effective for?

A

Hormone therapies aim to reduce the synthesis of steroid hormones and/or to anatagonise their role in signalling

Some breast cancers grow more rapidly in the presence of steroid hormone

Prostate cancers are stimulated by male steroid hormones

111
Q

Tamoxifen

A

Competitive antagonist of the oestrogen receptor in breast tissue

Effective against 70% of breast cancers and inhibits cell proliferation

BUT does cause an increase in endometrial proliferation (ER agonist)

112
Q

Toremifene

A

Competitive antagonist for oestrogen receptor

Used as an anti breast cancer drug

Improvement of Tamoxifen as it does not stimulate endometiral growth (ER agonism)

113
Q

Anastrazole

A

Aromatase enzyme inhibitor involved in the final step of the oestrogen synthesis pathway

Inhibits oestrogen synthesis in fat and muscle of post menopausal women

Used in the treatment of breast cancer

114
Q

Flutamide

A

Anti androgen drug that competes with testosterone for binding to the androgen receptor and inhibits cell proliferation

Used in the treatment of prostate cancer

115
Q

Goseraline

A

Synthetic homologue of gonadotropin-releasing hormone (GnRH) that acts as a strong agonist on the GnRH receptor

GnRH indirectly stimulates testosterone synthesis in testis (via LH), but sustained agonist binding at the GnRH receptor results in complete inhibition of testosterone synthesis

116
Q

Prednisone

A

Prodrug that is converted in the liver into prednisolone

-glucocorticoid agonist used in the treatment of acute lymphoblastic leukemia

117
Q

How can cancer cells have self-sufficiency in growth signals?

A

Overproduction of growth factors and or their receptors

118
Q

Trastuzumab

A

Binds to the ectracellular domain of human epidermal growth factor receptor 2

(this is over expressed in 25-30% of breast cancers)

119
Q

Cetuximab

A

Binds to extracellular domain of the human epidermal growth factor 1 receptor (EGFR) and prevents ligand binding

Used against colorectal cancer and head and neck cancer

120
Q

Bevacizumab

A

Inhibits human vascular endothelial growth factor (VEGF). This is require of tumours to create its own blood supply

Used in the treatment of metastatic colorectal cancer (with 5-fluorouracil), lung cancer and breast cancer

121
Q

Explain how Chronic Myeloid Leukemia comes to be

A

Translocation of ABL from chromosome 9 onto the Philadelphia chromosome next to BCR

Fusion protein of Bcr-Abl is expressed that contains a permanently activate tyrosine kinase (ABL1=oncogene)

122
Q

Imatinib

A

Small molecule inhibitor of tyrosine kinase

Also inhibits c-kit, a receptor tyrosine kinase which is over expressed in GI stromal tumours

123
Q

Erlotinib

A

Inhibits EGFR tyrosine kinase

Effective against lung cancers

124
Q

Imantib mesylate

A

Agent that specifically inhibits the BCR-ABL protein kinase activity, and it is active in chronic and blast phases of CML

Can also inhibit the tyrosine kinase activity of c-kit, which is commonly over-expressed in patients with GI stromal tumours

125
Q

What are the two forms of resistance?

A

Intrinsic - Inherent insensitivity to a drug

Acquired - Organisms that were originally sensitive become less sensitive or insensitive to a drug

126
Q

How can drug resistance be created experimentally?

A

By growing cells in sub-toxic drug concentrations then transferring the surviving cells to a slightly higher drug concentration and allow the cells to adapt again

127
Q

What the biochemical mechanisms of bacterial drug resistance?

A 
Enzyme inactivation (inside or outside)
Target modification
Enhanced DNA repair
Metabolic bypass/target replacement
Drug efflux/secretion
128
Q

How is resistance to antibiotics with a β-lactam ring achieved?

A

β-lactamases - hydrolyse 1000 penicilin molecules per second

129
Q

What are good examples of intrinsic resistance?

A

Failure of fungi to respond to rifampin (as drug cannot pass through fungal cell envelope)

Bacteria are resistant to ergosterol as they do not synthesise ergosterol

130
Q

Isoniazid

A

Inhibits the biosynthesis of mycolic acid

First line treatment against M.tuberculosis

131
Q

How do β-lactamases act to produce drug resistance?

A

Their active site allows free access of water and deacetylation is fast

132
Q

What are the classes of β-lactamases? Which one is different and why?

A

A, B, C and D

B is a zinc β lactamase

133
Q

What is the difference between zinc β-lactamases and other β-lactamases?

A

zinc does not involve an acyl intermediate

134
Q

How do aminoglycosides interact with their target? Why is this important in resistance?

A

Through the interaction of the OH and NH2 groups of the Aminoglycoside with the 16S rRNA in the 30S subunit via hydrogen bonds

The OH and NH2 groups are modified thus preventing this interaction

135
Q

How is resistance to aminoglycosides achieved?

A

N-acetylation of NH2 groups by acetyl-CoA

O-phosphoryl transfer of the γ-phosphate group of ATP to an OH moiety on the aminoglycoside

O-adenylyl transfer of the α phosphate group of ATP = addition of the AMP moiety to the OH moiety on the aminoglycoside

136
Q

How can pathogens alter the drug target to achieve drug resistance?

A

By mutation at one or more sites of the target gene

By enhancing expression of the target

By importation of a gene that specifies a new replacement enzyme with decreased sensitivity to drug

137
Q

Why was methicillin developed?

A

It bulky side chain group enhanced the lifetime of the covalent pennicillyol-O-lactamase acyl enzyme intermediate against hydrolysis

138
Q

What is MRSA resistant to?

A

Essentially all β-lactam molecules, including penicillins, cephalosporins, carbapenams, and penems

139
Q

How does MRSA achieve its resistance?

A

Through the expression of the mecA gene which encodes a new β-lactam-insensitive bifunctional transglycosylase/transpeptidase

In addition to it express the fem genes which confer a high level of β-lactam resistance when expressed in combo with mecA

140
Q

What is the function of the fem gene? What does fem stand for?

A

Its products add a pentaglycyl cross bridge with mixed glycine, alanine and serine residues

Produces resistance when expressed in combination of mecA

fem= factor essential for expression of methicillin resistance

141
Q

What is the product of the mec gene?

A

A β-lactam-insensitive, bifunctional transglycosylase/transpeptidase

142
Q

Which bacteria other than MRSA is showing resistance to multiple β-lactam drugs?

A

Streptococcus pneumonia

143
Q

How does streptococcus pneumonia achieve β-lactam resistance?

A

Through changes in the composition of PG transpeptidase and other penicillin-binding proteins

144
Q

Which bacterium is displaying effective resistance to vancomycin?

A

Enterococcus faecalis

145
Q

What are the clinical phenotypes of vancomycin resistant enterococcus faecalis?

A

VanA and VanB

146
Q

What is the difference between the two vancomycin resistant enterococcus faecalis phenotypes?

A

VanB has continuing sensitivity to glycopeptide teicoplanin (a vancomycin analogue)

147
Q

What is necessary and sufficient to produce the Vana/VanB phenotypes?

A

Five tandemly arranged genes:

Three enzymes involved in the reprogramming of the PG termini to D-acyl-D-Ala-D-lactate = VanH, VanA and VanX

Two proteins, VanS and VanR forming a two component signal transducer for inducible reprogramming to vancomycin resistance

148
Q

Resistance to which drug has been found in pneumococci?

A

Macrolides eg erythromycin, azithromycin and clarithromycin

149
Q

How is resistance to macrolides achieved? What else does this cause?

A

Methylation of A2058 in the 23S rRNA in the 50S ribosomal subunit by RNA methyltransferase

Also reduces affinity of the rRNA for lincosamides and streptogramin B, without affecting rRNA function

150
Q

In what species is reducing drug influx particularly effective and why?

A

Pseudomonsa aeruginosa because it takes in aminoglycosides by rapid facilitated diffusion through porin channels which are present in the outer membrane

151
Q

Why does pseudomonas achieve its resistance to aminoglycosides?

A

Reducing the number of porins that take up the drug by facilitated diffusion and by modifying the lipopolysaccharide outer leaflet which further reduces passive influx into the periplasm

Mutations in the uptake transporters that reduce the affinity for aminoglycosides or disable it can prevent its uptake from the periplasm into the cytoplasm

152
Q

What drug is often given in combination with β-lactam drugs in the treatment of S. aureus? Why?

A

Aminoglycosides

Because they can passively diffuse into the cell more easily due to the inhibition of cell wall synthesis

Helps to prevent the development of resistance by increasing the bactericidal action

153
Q

How does increasing the hydrophobicity of a drug help to prevent resistance?

A

Drug influx cannot be prevented due to the non-protein mediated diffusion

154
Q

How are hydrophobic drugs removed from cells?

A

By active drug efflux

155
Q

For which drugs is active drug efflux clinically relevant?

A

Β-lactams, macrolides, fluroquinolones, tetracyclines and many more

156
Q

How can the specificity of drug efflux transporters vary?

A

Can be specific to a single drug/ class of drug or can exhibit an extremely broad drug specificity

157
Q

What is an example of a transporter that is effective for a single drug?

A

The tetracycline transporter

158
Q

What are the two main ways by which bacteria can get a remarkable capacity to efflux drugs?

A

Chromosomally encoded metabolic capacity

Or by the acquisition of transport genes on plasmids and transposons

159
Q

What are the two kinds of drug transporter?

A

Primary - ATP hydrolysis

Secondary - Mediate the outward movement of drugs to the inward movement of ions (H+/Na+)

160
Q

Generally speaking within which organisms use the two kinds of drug transporter?

A

Primary is mainly used by eukaryotes

Secondary is more commonly used by prokaryotes

161
Q

What is the general structure of the drug transporters found in Gram negative bacteria?

A

Secondary active transporter often associated with an accessory protein which spans the periplasm, and an outer membrane porin to allow drug transport across the cell envelope

162
Q

What is multiple drug resistance?

A

The simultaneous expression of various antibiotic resistance mechanisms, each specific for a drug or class of drugs

They genes can be activated by regulon

163
Q

What is multidrug resistance?

A

The presence of a multidrug efflux pump in the plasma membrane confers resistance to a wide variety drugs due to the enormously broad specificity of the pump

164
Q

How can resistance to azoles arise?

A

Alterations in the activity and amount of enzymes involved in ergosterol biosynthesis

Active azole efflux

165
Q

How is resistance to purine analogues achieved?

A

Changes in the substrate specificity of the viral purine-activating thymidine kinase, disabling the phosphorylation of purine analogues.

166
Q

How is resistance to reverse transcriptase inhibitors or protease inhibitors achieved?

A

Due to mutations in these enzymes that disable the interaction between enzyme and inhibitor

167
Q

How is chloroquine resistance achieved?

A

Through less efficient accumulation of chloroquine in their food vacuoles = exclusion of the drug from the site of action

Found to be the result of pumping the drug out - either by an ATP-dependent P-glycoprotein or CRT (chloroquine resistance transporter)

168
Q

How can drug resistance be achieved in cancer?

A

1) Drug detoxification by cytochrome p450 systems (CyP450) and on conjugation by glutathione S-transferase and other conjugating systems
2) Mutations in drug targets
3) Increases in DNA repair pathways
4) Metabolic bypass
5) Drug efflux by multidrug transporters

169
Q

Give an example of how cancers can develop resistance to drugs via mutations in drug targets

A

Cells resistant to topo poisons (eg etoposides) possess modified topoisomerases

170
Q

Give examples of how cancers can develop resistance to drugs via an increases in DNA repair pathways.

A

Nitrosurea resistant cells have high levels of alkyltransferases that repair guanine lesions and so prevent DNA cross-linking

Cisplatin resitnat cells have higher levels of enzymes involved in DNA repair

171
Q

Give an example of how cancers can develop resistance to drugs through metabolic bypass

A

Methotrexate reistance can be based on enhanced expression of dihydrofolate reductase

(can also result from reduced uptake due to mutations in the folate carrier which reduces the affinity for methotrexate)

172
Q

Give examples of some drug efflux pumps used by cancer cells

A

Multidrug resistance P-glycoprotein MDR1

Multidrug resistance associated proteins (MRP1, MRP2)

Breast cancer resistance protein (ABCG2)

173
Q

What are the strategies used to combat drug resistance?

A

Identification of new drug targets

Specific inhibitors of drug resistance mechanisms

Combination therapies

Extending antibiotic lifespan

174
Q

What is the current mechanism used for identifying new drug targets

A

Sequencing the genome and looking for essential for survival/virulence

Then tests their protein products against inhibitors

Potential inhibitors can then be tested in vitro and vivo

175
Q

Give some examples of specific inhibitors of drug resistance mechanisms

A

Clavunate = suicide substrate for β lactamase (used in augmentin)

Sulbactam forms covalent acyl intermediate with β lactamase (used in Unasyn)

176
Q

Augmentin

A

Combination of amoxicillin (β lactamase) and clavulanate (β lactamase inhibitor)

177
Q

Ly333328

A

Semisynthetic analogue of vancomycin
Contains a hydrophobic biphenyl substituent on the vancosamine sugar and is more hydrophobic and pay partition the analogue more to the membrane, as well as alter its ratio of inhibition between transpeptidases and transglycosylase

178
Q

Oxazolidinones

A

New class of antibiotic with broad spectrum

Also inhibit protein biosynthesis, specifically by interaction with the 23S ribosomal RNA of the 50S subunit (at or near the peptidyl transferase centre)

179
Q

Linezolid

A

Oxazolidinone

Interacts with the 23S ribosomal subunit of the 50S subunit at or near the peptidyl transferase centre of the ribosome

180
Q

Why is combination therapy so effective?

A

Because it reduces the chance of them developing resistance

181
Q

What are the attempts to extend anitbiotic lifespans (preventing resistance)

A

Judicious use of antibiotics

Rotating the use of antibiotic

182
Q

How can PARP inhibitors be used as anti-cancer drugs?

A

PARP = single strand repair

Therefore is BRCA2 is not functioning then blockage of PARP = cell death

183
Q

BMN-673

A

PARP inhibitor in Phase III clinical trials for BRCA2 mutated breast cancer

185
Q

Olaparib

A

A PARP inhibitor in phase III clinical trials

186
Q

Isoniazid

A

First-line medication used to treat TB

Inhibits the biosynthesis of mycolic acid in Mycobacterium tuberculosis

187
Q

Bacitracin

A

Cyclic polypeptide antibiotic

Forms a tight complex with Mg2: and bactoprenol phosphate

Inhibits the dephosphorylation to bactoprenol phosphate

188
Q

Clavulanate

A

A β lactamase inhibitor used in combination with amoxicilin

189
Q

Aminocoumarins

A

Class of antibiotics that act by inhibiting type II DNA topoisomerases

190
Q

Nystatin

A

Antibiotic/antigunal agent

Binds to the sterol ergosterol and facilitates the formation of pores

191
Q

Fluconazole

A

Triazole antigunal drug

Inhibits ergosterol biosynthesis

192
Q

Miconazole

A

Imidazole antifungal and antiprotozoal drug

Inhibits ergosterol biosynthesis

193
Q

HAART

A

Combination of nevirapine, zidovudine and saquinavir used to treat serious manifestations of HIV infections in patients with AIDS

MODA (8 decks)

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